Reversible mitochondrial infantile liver failure with hemophagocytic lymphohistiocytosis associated with a TRMU gene mutation

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Mitochondrial diseases are a clinically heterogeneous group of multisystem disorders caused by mitochondrial dysfunction. Hepatic involvement is a common feature in neonatal mitochondrial hepatopathies, which may manifest as acute liver failure, hepatic steatohepatitis, cholestasis, or even as chronic liver failure of insidious onset. Mitochondrial diseases are usually severe and rapidly progressive conditions and eventually fatal. However, some of the rare forms show remarkable spontaneous recoveries. The diagnostic process is complex, requiring clinical, biochemical, histological, and genetic investigations. Mutations in several mitochondrial DNA (mt-DNA) and nuclear genes involved in mt-DNA stability and mitochondrial protein synthesis machinery have been associated with mitochondrial disorders. Recently, mutations of TRMU gene encoding mitochondrial tRNA-specific 2-thiouridylase defines the pathomechanism of mitochondrial protein translation defect in the neonatal period presenting with early-onset, reversible liver disease. Here, we report the clinical, biochemical, and genetic findings from one Arab Yamani child presenting with hepatopathy, hyperlactatemia and respiratory chain defect associated with hemophagocytic lymphohistiocytosis, a feature which has not been described in previously reported cases. The aim was to have a prompt definitive genetic diagnosis to provide timely clinical management, decrease morbidity, and improve the survival of the patient. Utilizing next-generation sequencing techniques we identified the pathogenic biallelic mutation c.835G>A (p.Val279Met) in TRMU gene by whole exome sequencing. Since spontaneous recovery is a rare feature in mitochondrial liver disorders, early identification of underlying TRMU mutation can influence clinical management decisions. Our results add to the repertoire of a small number of cases with TRMU mutations reported in mitochondrial liver diseases, for further elaboration of genotype-phenotype correlation.